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Outcome of allo-SCT for chronic myelomonocytic leukemia

Chronic myelomonocytic leukemia (CMML) is a rare heterogeneous malignancy with an annual incidence of 13:100 000 occurring predominantly >65 years of age. The phenotype varies from myelodysplastic to myeloproliferative features, and the clinical course is heterogeneous.1 Treatment strategies are expanding because of new compounds, for example, lenalidomide2 or intensive chemotherapy for advanced stages,3 and increasing numbers of patients receive allogeneic haematopoietic SCT from related/unrelated donors facilitated by reduced intensity conditioning (RIC).4 The design of guidelines based on the individual risk profiles is difficult in CMML,5 as its rare heterogenous presentation hampers the evaluation of larger samples. To contribute to insights in the outcome of SCT in this rare disorder, we retrospectively analyzed 12 consecutive CMML patients receiving 13 allogeneic SCT at the University of Hamburg, Germany, from January 2003 to June 2007.

All 12 patients gave informed consent. Some patients were included in a previous study.6 One patient (no. 1) received two allo-SCTs from two different unrelated donors. Eleven patients had unrelated donors (six HLA matched, five mismatched in the HLA-DQB1-alleles), and two received SCT from HLA-identical siblings. All 13 transplants were performed with PBSCs (mean dose 7.65 × 106 CD34+/kg; range 3.9–11.34). The CMV status was the same in 12 donor/recipient pairs (Table 1).

Table 1 Characteristics of 12 patients with CMML receiving 13 allo-SCTs (patient no. 1 received two allo-SCTs)

Eight patients had CMML-1 and four CMML-2; patient no. 1 with two SCTs showed CMML-2 also at relapse. Only two transplantations were performed in CR after previous chemotherapy. Four transplants were performed in therapy-refractory patients. Allo-SCT was upfront strategy in seven cases. The median interval from diagnosis to transplantation was 7 months (range 1–36). Cytogenetics were available in 11 cases and revealed seven normal karyotypes; the remaining four patients showed complex aberrations, +5 and −9, +21 and del(17q), and one t(3;3)(q21;q26).

Myeloablative conditioning was performed in seven and reduced conditioning in six cases. Myeloablative conditioning regimens consisted of i.v. BU (cumulative doses 10.4–14 mg/kg) combined in all cases with CY (120/mg/kg) and in six cases with etoposide (30 mg/kg). Antithymocyte globulin was used in five patients (ATG Fresenius; 30–90 mg/kg, or ATG Merieux, 8 mg/kg).

Reduced conditioning was performed according to the FLAMSA protocol7 (cumulative doses−fludarabine 120–180 mg/m2, amsacrine 400 mg/m2, cytarabine 8000 mg/m2) in five patients in combination with i.v. BU (6.4 mg/kg) or CY (120 mg/kg) and TBI (4 Gy). The sixth patient received treosulfan (30 mg/m2). All patients received antithymocyte globulin with cumulative dosages of 6–8 mg/kg.

Immunosuppression was performed by CsA from day −1 over 6 months (serum level 140–220 ng/ml), combined with MTX (10 mg/mg2; days +1, +3, +6) in myeloablative conditioning, or with mycophenolate mofetil in reduced conditioning. G-CSF was maintained from day +5 until granulocytes exceeded 1.0 × 109/l.

The median age at diagnosis of CMML was 56 years (range 37–66 years). Four patients (all after myeloablative conditioning) developed hepatic veno-occlusive disease of the liver. Acute GVHD (I–IV) was seen in 10 of the 13 cases (77%). Severe GVHD (II–IV) occurred in six cases (46%), in four cases after reduced, in two after myeloablative conditioning. Chronic GVHD was seen in 5 of 10 patients (50%) who survived >day 100 (limited in three patients; extensive in two patients)—in three cases after RIC, in two after myeloablative conditioning.

Nine of twelve patients are alive after a median follow-up of 26 months (range 5–40 months) following SCT. The probability of overall survival was 75% (95% confidence interval (CI): 50–100%) (Figure 1a). Three patients (nos. 2, 4, 9) died because of TRM from severe GVHD or sepsis on days +37, +47 and +82 after myeloablative conditioning. Both patients with grade IV acute GVHD (nos. 4, 9) were transplanted from HLA DQB-mismatched unrelated donors and had received antithymocyte globuline (no. 4: ATG Fresenius; 60 mg/kg; patient no. 9: ATG Merieux/thymoglobuline; 8 mg/kg). One patient (no. 1) had two allo-SCTs (myeloablative/RIC) from two different donors and is still alive.

Figure 1
figure1

(a) Kaplan–Meier curves showing a 75% probability of overall survival (95% CI: 50–100%) and (b) and a 50% probability of disease-free survival (95% CI: 15–85%).

Two patients (nos. 1, 5) (both with CMML-1) relapsed 5 and 38 months after SCT, but are still alive after myeloablative conditioning and RIC. In more detail, the first patient who relapsed (no. 1) 38 months after the first SCT received a second allograft from a different matched unrelated donor after RIC, and at the time of this report—2 months from allo-SCT, he was still in remission. Before relapse, he had maintained complete donor chimerism. The other patient showing relapse (no.5) 5 months from SCT had a decrease of chimerism to 38%, so donor lymphocytes were planned at the time of this report. Thus, there was a relapse rate of 17%. The probability of disease-free survival was 50% (95% CI: 15–85%), and the probability of 2-year disease-free survival was 67% (40–94%; Figure 1b).

Four of seven patients who are alive in stable remission at the time of this report have a good quality of life, whereas three of these patients are disabled by severe sicca syndrome of the eyes. Six patients with myeloablative conditioning achieved full-donor chimerism, whereas in the RIC group, full-donor chimerism was achieved in four of six cases with available data.

At present, specific guidelines for indications and conditioning strategies are missing in the management of CMML because of its heterogeneity and rarity: Only limited numbers of CMML patients received allografts so far, and most studies evaluate the disorder in combination with other MDS/CMPD subtypes. In this study, we analyzed 12 consecutive CMML patients who received 13 allogeneic SCTs in the last 4 years.

First, overall survival was 75% and the relapse rate was 17% in this analysis. Earlier studies reported relapse rates of 23–42% after allo-SCT.5, 8, 9 However, the limited follow-up period with a median of 26 months in this study has to be considered. Thus, SCT leads to considerable rates of stable remissions in selected patients even with CMML-2. Here, RIC did not seem correlated with an increased relapse rate, but the limited case number does not allow definite conclusions.

Second, this and earlier studies showed high day 100-TRM after SCT in CMML: 25% in this study, 35% in an EBMT study5 and 41% in another report.8 Severe GVHD grades II–IV and III–IV occurred in 46 and 23% of transplantations, which was comparable to 35–75% and 23–37% in earlier analyses.5, 8 Severe acute GVHD was a major cause of TRM in this and the other studies.5

Whether the outcome in CMML might be improved by RIC7 remains to be further evaluated. Recently, Laport et al.10 published a study on the role of RIC in patients with diverse myeloid malignancies including seven CMML patients with promising results, as three of seven patients (43%) were free of disease after a follow-up of 3 years. Thus, although the limited number of patients analyzed so far in this study and in earlier studies has to be taken into account, allo-SCT may be a good option for selected CMML patients and may result in a plateau of disease-free survival that cannot be achieved by other treatment strategies.

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Ocheni, S., Kröger, N., Zabelina, T. et al. Outcome of allo-SCT for chronic myelomonocytic leukemia. Bone Marrow Transplant 43, 659–661 (2009). https://doi.org/10.1038/bmt.2008.366

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